Does Light Therapy Increase the Risk for Cancer in Kids?

Veronica Hackethal, MD

May 25, 2016

Phototherapy may or may not increase the risk for pediatric cancer, according to two new large studies published online May 23 in Pediatrics. Given the equivocal nature of the results, the authors and editorialists urge caution.

Both studies used a Big Data approach to address the question, but although one study found a statistically significant link between phototherapy and pediatric cancer, the absolute risk remained small; the other study also showed a link, but the results lost statistical significance after adjusting for confounders.

"Our results support the need for health care providers to consider phototherapy as they do most other treatments (ie, as having both benefits and potential risks) and to limit the use of phototherapy to infants for whom the benefit/risk balance is most likely to be favorable," write Andrea Wickremasinghe, MD, from the University of San Francisco in California and Kaiser Permanente Northern California, Santa Clara, and colleagues in the first study.

Phototherapy has long been standard treatment for hyperbilirubinemia of newborns, which can cause deafness and brain damage (kernicterus) when severe and untreated. The use of phototherapy has increased in recent years, perhaps because of better identification of infants with hyperbilirubinemia, fear of kernicterus, the general assumption that phototherapy is safe, and the use of light therapy units at home.

Since the 1970s, phototherapy has been linked to DNA damage. Epidemiological studies, however, have shown mixed results with links to cancer.

In the second study, called the Late Impact of Getting Hyperbilirubinemia or Phototherapy (LIGHT), Thomas Newman, MD, MPH, from the University of California, San Francisco, and Kaiser Permanente Northern California, Oakland, and colleagues analyzed data from 499,621 children born at 35 weeks' gestation or older in the Kaiser Permanente Northern California network of hospitals between 1995 and 2011. Both inpatient and home light therapy were included in the analysis.

Overall, the use of phototherapy increased from 2.7% in 1995 to 15.9% in 2011. Because of that increase, the median follow-up time was shorter for those who had light therapy (6.2 ± 4.3 years) compared with for those who did not (8.3 ± 5.2 years).

During follow-up, 711 children were diagnosed with cancer, including 60 among those exposed to light therapy (24.6 per 100,000 person-years) and 651 among those who did not have light therapy (17.2 per 100,000 person-years).

Newborns who received phototherapy had increased rates of any type of leukemia (incidence rate ratio [IRR], 2.1; P = .0007), nonlymphocytic leukemia (IRR, 4.0; P = .0004), and liver cancer (IRR, 5.2; P = .04) compared with unexposed children.

However, after adjusting for bilirubin levels, chromosomal disorders, congenital anomalies, and other potential confounders, the link between phototherapy and cancer lost statistical significance.

Down syndrome was one of the strongest risk factors for cancer and leukemia. Other factors linked to increased cancer risk included high birth weight, 5-minute Apgar score lower than 7, and other chromosomal and congenital anomalies.

"The key question is therefore whether the association is entirely due to confounding, that is, to one or more factors that cause both phototherapy and cancer (particularly leukemia)," the authors write. They note, for example, that Down syndrome is strongly associated with both leukemia and receipt of phototherapy.

Despite the possibility that confounding explains at least part of the association, the authors still note a "striking" early increase in nonlymphocytic leukemia and urge caution regarding the use of phototherapy, at least in children at increased risk for cancer, such as those with Down syndrome.

"The likelihood of harms exceeding benefits is greatest in children with Down syndrome, whose much higher baseline risk of leukemia might lead cautious clinicians to increase the treatment threshold for initiation of phototherapy in these infants, despite the fact that the association between phototherapy and cancer has not yet been proven to be causal," Dr Newman and colleagues write.

Infantile Cancer Incidence Elevated

In the California Late Impact of Phototherapy Study (CLIPS) by Dr Wickremasinghe and colleagues, the authors analyzed data from 5,144,849 infants born at age 35 weeks' gestation or older in California hospitals between 1998 and 2007. They used data from the California Office of Statewide Health Planning and Development and administrative data linked to billing codes and hospital discharge records to identify children who had received phototherapy and those diagnosed with cancer before their first birthday.

As in the study by Dr Newman and colleagues, the CLIPS researchers found that use of phototherapy increased during the study period, going from 2.9% in 1998 to 4.4% in 2007 (P < .001).

Overall, 1100 infants were diagnosed with cancer, including 58 of those who received light therapy (32.6 per 100,000) and 1042 of those who did not receive phototherapy (21.0 per 100,000).

Propensity-adjusted analyses, which included potential confounders associated with phototherapy, showed a statistically significant link between phototherapy and overall cancer (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.1 - 1.9), myeloid leukemia (aOR, 2.6; 95% CI, 1.3 - 5.0), and kidney cancer (aOR, 2.5; 95% CI, 1.2 - 5.1).

As in the LIGHT study, children with Down syndrome appeared to be particularly vulnerable to the ill effects associated with phototherapy. "The marginal propensity-adjusted absolute risk increase for cancer after phototherapy was much higher for infants with Down syndrome (77.8/100 000; 95% CI, −1.2/100 000–156.8/100 000, number needed to harm of 1285) than for infants without Down syndrome (8.1/100 000, 95% CI 0.4/100 000–15.8/100 000, number needed to harm of 12 346)."

The authors emphasize that phototherapy has decreased the need for exchange transfusions, which carry up to a 1.9% risk for mortality. However, they also note that having bilirubin levels near the threshold for exchange transfusion is often benign, and that the number of children needed to treat to prevent one transfusion varies widely.

Weighing Risks and Benefits

In a linked commentary, A. Lindsay Frazier, MD, from the Dana-Farber/Boston Children's Cancer and Blood Disorders Center in Boston, Massachusetts, and colleagues emphasize the rarity of childhood cancer, which limits the ability of researchers to detect associations among environmental, genetic, and other factors that may influence its development. Large data sets are necessary, although even with the Big Data approach, the actual number of pediatric cancer cases remains small.

Nevertheless, despite the shortcomings of researching a rare disease, the commentators also advise caution.

"In the end, acknowledging that the information is imperfect, general pediatricians and neonatologists must make a choice. These data suggest that phototherapy may not be harmless, and that the risks as well as the benefits need to be weighed before flipping the switch," they conclude.

The study by Dr Newman and colleagues was supported by a grant from the Agency for Healthcare Research and Quality. The study by Dr Wickremasinghe and colleagues was supported by a Gerber Foundation Novice Research Award and American Academy of Pediatrics Marshall Klaus Perinatal Research Award to Dr Wickremasinghe. The authors of both studies and the commentators have disclosed no relevant financial relationships.

Pediatrics. Published online May 23, 2016. Wickremasinghe full text, Newman full text, Commentary full text

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